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Trial record 1 of 1 for:    NCT01959698
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Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma

This study is currently recruiting participants.
Verified July 2017 by Roswell Park Cancer Institute
Sponsor:
ClinicalTrials.gov Identifier:
NCT01959698
First Posted: October 10, 2013
Last Update Posted: July 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute
  Purpose
This phase I/II trial studies the side effects and best dose of carfilzomib when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well it works in treating patients with stage I-IV diffuse large B-cell lymphoma that has returned (relapsed) or that has not responded to treatment (refractory). Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, also work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be a better treatment for diffuse large B-cell lymphoma.

Condition Intervention Phase
CD20 Positive Recurrent Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Stage I Diffuse Large B-Cell Lymphoma Stage II Diffuse Large B-Cell Lymphoma Stage III Diffuse Large B-Cell Lymphoma Stage IV Diffuse Large B-Cell Lymphoma Drug: Carboplatin Drug: Carfilzomib Drug: Etoposide Drug: Ifosfamide Other: Laboratory Biomarker Analysis Other: Pharmacological Study Biological: Rituximab Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus Carboplatin Plus Etoposide (C-R-ICE) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Resource links provided by NLM:


Further study details as provided by Roswell Park Cancer Institute:

Primary Outcome Measures:
  • Best overall response rate (PR + CR) (Phase II) [ Time Frame: The time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented, assessed up to 12 weeks ]
  • MTD defined as the dose of carfilzomib added to standard R-ICE chemotherapy which, if exceeded, would put the patient at an undesirable risk of medically unacceptable dose-limiting toxicities (Phase I) [ Time Frame: 28 days ]

Secondary Outcome Measures:
  • Complete response rate according to the International Working Group Response criteria as reported by the revised Cheson criteria [ Time Frame: Up to 5 years ]
    Efficacy rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson. The relationship between binary outcomes and collected demographic and baseline variables will be statistically assessed using logistic regression.

  • Overall survival [ Time Frame: From the start of treatment until death for any reason, assessed up to 5 years ]
    The estimated distributions of overall survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

  • Pharmacokinetics (PK)/pharmacodynamics (PD) of carfilzomib and standard R-ICE combination therapy in adult patients with relapsed/refractory diffuse large B-cell lymphoma [ Time Frame: Pre-dose, just prior to the end of the infusion; and at 15 minutes, 30 minutes, 1, 2, 4, 6 hours post infusion on course 1, day 1, then at 24 hours post course 1 infusion on course 1, day 2 (prior to day 2 infusion) ]
    A population PK/PD structural model will be developed for carfilzomib based on degree of proteasome inhibition in relation to efficacy and toxicity endpoints in the proposed study using NONMEM. This model will describe the potential relationship between carfilzomib exposure in relation to proteasome inhibition to the time course of thrombocytopenia and neutropenia as indicators of pharmacodynamics response.

  • Progression-free survival [ Time Frame: Up to 5 years ]
    The estimated distributions of progression-free survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.

  • Toxicity of the addition of carfilzomib to R-ICE at the MTD, assessed by the CTEP version 4.0 of the NCI CTCAE [ Time Frame: Up to 5 years ]
    Toxicity rates will be estimated using simple relative frequencies. The corresponding 95% confidence intervals for the estimated probabilities will be computed using the method proposed in Clopper and Pearson. The relationship between binary outcomes and collected demographic and baseline variables will be statistically assessed using logistic regression.


Other Outcome Measures:
  • Degree of proteasome inhibition determined by enzymatic assay for chymotrypsin-like activity [ Time Frame: Days 1-3 of course 1 ]
  • Ex vivo analysis of sensitivity of primary tumor cells to various combinations of carfilzomib versus bortezomib +/- rituximab [ Time Frame: Baseline ]
  • Functional activity of patients peripheral blood mononuclear "effector" cells [ Time Frame: Baseline ]

Estimated Enrollment: 73
Actual Study Start Date: April 17, 2014
Estimated Study Completion Date: July 15, 2020
Estimated Primary Completion Date: July 15, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (carfilzomib, rituximab, chemotherapy)
Patients receive carfilzomib IV over 10-30 minutes on days 1, 2, 8, and 9; rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplat
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
Drug: Carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171
Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213
Drug: Ifosfamide
Given IV
Other Names:
  • Asta Z 4942
  • Asta Z-4942
  • Cyfos
  • Holoxan
  • Holoxane
  • Ifex
  • IFO
  • IFO-Cell
  • Ifolem
  • Ifomida
  • Ifomide
  • Ifosfamidum
  • Ifoxan
  • IFX
  • Iphosphamid
  • Iphosphamide
  • Iso-Endoxan
  • Isoendoxan
  • Isophosphamide
  • Mitoxana
  • MJF 9325
  • MJF-9325
  • Naxamide
  • Seromida
  • Tronoxal
  • Z 4942
  • Z-4942
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • RTXM83

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histological confirmation of relapsed/refractory CD20 positive diffuse large B-cell lymphoma
  • Ann Arbor stage I to stage IV DLBCL at the time of relapsed/refractory disease to be eligible
  • Measurable or assessable disease is required; measurable tumor size (at least one node measuring 2.25 cm^2 in bidimensional measurement) per computed tomography (CT) scan, other radiological study, and/or physical exam
  • Patients must have received at least 1 prior rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, etc.)
  • >= 2 weeks since major surgery
  • Patients must not have any significant toxicity associated with prior surgery, radiation therapy, chemotherapy, or immunotherapy, per principal investigator (PI) discretion
  • Life expectancy >= 3 months
  • Karnofsky score (KS) >= 50
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3.5 times the upper limit of normal within 14 days prior to starting therapy
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L within 14 days prior to starting therapy*
  • Hemoglobin >= 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)*
  • Platelet count >= 50 x 10^9/L (>= 20 x 10^9/L if lymphoma involvement in the pretreatment bone marrow is found) within 14 days prior to starting therapy*
  • *Note: If patient has cytopenias due to bone marrow involvement, these requirements are not applicable
  • Serum creatinine of =< 1.5 mg/dL; if creatinine > 1.5 mg/dL creatinine clearance must be > 60 mL/min within 7 days prior to treatment either measured or calculated using a standard Cockcroft and Gault formula
  • Written informed consent in accordance with federal, local, and institutional guidelines
  • Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Male subjects must agree to practice contraception
  • No known hypersensitivity to murine products
  • Patients must have normal baseline cardiac function based upon echocardiogram or gated blood pool scan (multigated acquisition scan [MUGA]) with an ejection fraction >= 50%
  • Patients who test positive for hepatitis C (HepC) antibodies (Ab) are eligible provided all of the following criteria are met: bilirubin =< 2 x upper limit of normal; ALT/AST =< 3 x upper limit of normal; and clinical evaluation to rule out cirrhosis
  • Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL based on hepatitis B serological testing as follows:

    • Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb) negative, hepatitis B surface antibody (HBsAb) positive patients are eligible
    • Patients who test positive for HBsAg are ineligible (regardless of other hepatitis B serologies)
    • Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status) should have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing done and protocol eligibility determined as follows:

      • If HBV DNA is positive, the subject will be excluded from the study
      • If HBV DNA is negative, the subject may be included but must undergo at least every 2 months HBV DNA polymerase chain reaction (PCR) testing from the start of treatment throughout the duration the treatment course

Exclusion Criteria:

  • Patients with non-Hodgkin lymphoma (NHL) other than DLBCL; including "transformed" DLBCL
  • Known to be seropositive for human immunodeficiency virus (HIV); an HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk
  • Positive serology for HBV defined as a positive test for HBsAg; in addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HepB DNA test will be performed and if positive the subject will be excluded
  • Patients with symptomatic brain involvement
  • Peripheral neuropathy of grade 2 or greater severity as defined by the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0; patients with grade 2 or higher (NCI-Common Toxicity Criteria [CTC]) neuropathy
  • Myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemia
  • Uncontrolled intercurrent illness including, but not limited to, active infection, poorly controlled hypertension, diabetes mellitus or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study
  • Pregnant or breastfeeding
  • Patient has received other investigational drugs within 4 weeks before enrollment
  • Chemotherapy within 3 weeks of the first scheduled study treatment
  • Less than 2-years disease free from another primary malignancy (other than squamous or basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast, superficial bladder carcinoma, or previously treated localized prostate cancer with normal prostate-specific antigen [PSA] levels); patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, are considered by their physician to be at less than 30% risk of relapse and at least 2 years have lapsed
  • Major surgery, other than diagnostic surgery, within 2 weeks
  • Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
  • Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent)
  • Prior high-dose chemotherapy (HDC)-ASCT
  • Active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating DLBCL at the time of registration to this study is not exclusion for study enrollment
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01959698


Locations
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Roswell Park    877-275-7724    ASKRPCI@RoswellPark.org   
Principal Investigator: Francisco J. Hernandez-ILizaliturri         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Investigators
Principal Investigator: Francisco Hernandez-ILizaliturri Roswell Park Cancer Institute
  More Information

Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT01959698     History of Changes
Other Study ID Numbers: I 240813
NCI-2013-01784 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 240813 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
R01CA136907 ( U.S. NIH Grant/Contract )
First Submitted: October 8, 2013
First Posted: October 10, 2013
Last Update Posted: July 11, 2017
Last Verified: July 2017

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Etoposide phosphate
Isophosphamide mustard
Carboplatin
Rituximab
Etoposide
Ifosfamide
Podophyllotoxin
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating